The candidate is a neuropathologist with a career goal of being a physician-scientist. His long-term research goal is to study the biological basis of behavior and cognitive function using mouse models. He is particularly interested in the epigenetic regulation of these processes. Despite increasing evidence for its importance, the role of epigenetics in behavior and cognition is currently poorly understood and under-studied. The candidate wishes to bridge the gap between these two disciplines. His immediate objective is to acquire a solid training in mouse genetics and epigenetics by studying an important epigenetic phenomenon, X-chromosome inactivation (XCI). XCI is a mammalian dosage compensation mechanism by which one of the two X-chromosomes in females is transcriptionally silenced. XCI enables females (XX) and males (XY) to achieve equal X-chromosome dosage despite unequal X chromosome number. XCI plays many important roles in developmental biology, such as spermatogenesis, placental development, and stem cell research. Thus, understanding the mechanisms of XCI has broad implications for medical science and human health. XCI is particularly appealing to the candidate as it serves as a controlling mechanism over many X-linked genes that are involved in central nervous system development and cognitive functions. XCI is carried out by the X-inactivation center (Xic), a cis-acting locus with many noncoding genes. One critical noncoding gene is Xist, which makes a 15 kb transcript expressed from the inactive X (Xi) and "coats" the Xi in cis. Xist is controlled by its antisense partner, Tsix, which opposes X-silencing and designates the X as the future active X. Tsix works together with another noncoding gene, Xite, which in part acts as an enhancer of Tsix. At least one other noncoding gene lies at the Xic. 'Jpx'('just proximal to Xist') lies 10 kb upstream of Xist and is well conserved in mammals. Because it lies within a 30 kb region previously shown to be important for the regulation of XCI, this application will test its potential function and mechanisms of action by deleting the Jpx gene in mice.